Suggesting mouse is not human…..in more ways than one
Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease.Proc Natl Acad Sci U S A. 2018 Sep 7. pii: 201810470.
The anti-CD20 antibody ocrelizumab, approved for treatment of multiple sclerosis, leads to rapid elimination of B cells from the blood. The extent of B cell depletion and kinetics of their recovery in different immune compartments is largely unknown. Here, we studied how anti-CD20 treatment influences B cells in bone marrow, blood, lymph nodes, and spleen in models of experimental autoimmune encephalomyelitis (EAE). Anti-CD20 reduced mature B cells in all compartments examined, although a subpopulation of antigen-experienced B cells persisted in splenic follicles. Upon treatment cessation, CD20+ B cells simultaneously repopulated in bone marrow and spleen before their reappearance in blood. In EAE induced by native myelin oligodendrocyte glycoprotein (MOG), a model in which B cells are activated, B cell recovery was characterized by expansion of mature, differentiated cells containing a high frequency of myelin-reactive B cells with restricted B cell receptor gene diversity. Those B cells served as efficient antigen-presenting cells (APCs) for activation of myelin-specific T cells. In MOG peptide-induced EAE, a purely T cell-mediated model that does not require B cells, in contrast, reconstituting B cells exhibited a naive phenotype without efficient APC capacity. Our results demonstrate that distinct subpopulations of B cells differ in their sensitivity to anti-CD20 treatment and suggest that differentiated B cells persisting in secondary lymphoid organs contribute to the recovering B cell pool.
as it will do me no favours, but it is by opinion-leaders and it does seem to rubbish our ideas and the story we have been creating concerning memory B cells and MS.…
Or Does it.
(However as they are not even cited L they may not be aware of them because they are not reading other peoples papers L because the literature review was not good enough or they are simply ignoring themL)
We have made the suggestion that cells within the memory B cell compartment are the important cell types targeted by CD20- depletion in MS and other conditions and recently it has been shown in MS that the memory B cell population presents antigen to T cells in MS. Yet here they report inhibition of EAE with CD20 depletion despite an increase in CD27+ (memory cell marker in humans) cells. So it deserves comment…
So here is some of the data
cannot be addressed in humans”.
- First, we established that a
fraction of mature B cells in the spleen is resistant to anti-CD20.
- Second, we
determined that, after cessation of treatment, splenic and bone-marrow B cells
reconstitute in parallel, substantially preceding B cell reappearance in
- Third, we observed that, in a model involving activated B cells,
the post–anti-CD20 B cell pool contained an elevated frequency of
differentiated, myelin-reactive B cells. Together, our findings reveal
mechanisms by which pathogenic B cells may persist in anti-CD20 treatment”.
humans……..But it does! Or maybe they are saying CD20 depletion should not work in mice.
that you can actually address these questions in humans”
However, you know me too well. So off we go….
they see an increase in CD27+ cells in both myelin oligodendrocyte glycoprotein (MOG) protein and MOG peptide induced
would say “So what! What does it tell us?”
Not much, as disease activity will not resume in the
C57BL/6 mouse model no matter what happens to the cells, so we can’t determine the consequences of the changes.
The kinetics of B cell repopulation in the blood of humans is known.
repletion response with immature and then mature B cells showing repopulation,
probably from the bone marrow. There is a marked depletion of memory B cells in
virtually every study (see above). The mature (naïve) B cells is not the
found there was a reduced diversity of repertoire, suggesting that the B cells
are initially repopulated from surviving B cells (I say….Surprise, Surprise?) but the
repertoire that survives is different. This is seen in MS (There are a number of studies on this but they were not cited in the discussion..Therefore so much for putting your work into the context of what is known).
antigen presenting function and they suggest that there are more autoreactive
cells. Surely this is opposite of what you would think you would want. Therefore what are these studies actually telling us…..I suppose that mouse studies are not going to give us a useful answer?
short-term treatment. In mice there is no long-term benefit. So is the rapid repopulation by pathogenic cells the reason why there is no long-term treatment
effect in mice?
Maybe, but I suspect not. In the C57BL/6 mice used, the attack causes nerve loss and this
does not recover. Hence you get the the flat-lining of the clinical disease. The data tells us
that the net result of a short term treatment of mice with CD20-depleting
antibody, whether it is MOG protein or MOG peptide means nothing in the long-term (See below).
many other papers.
The referee/editor buys into this and impact factor ten paper
here we come.
However, I have to say that “I hope the authors do not do their animal
experiments/pathology like their literature reviewsJ“
Simply read the paper above to see this.
controlled as the animal experiments, what goes on in human lymph nodes/tonsils,
spleen, blood and bone marrow following rituximab.
purpura and this has occurred after rituximab, as have lymph node and bone
marrow biopsies. So the discussion of the paper is rather lacking to say the
“I’m just being constructive here”.
mouse B cell biology is not the same, perhaps because human B cell biology is
heavily influenced by Epstein Barr Virus, which does not infect rodents.
of CD27, but this appears not to be the case in mice, seemingly ignored by the
authors of this paper, who imply they are detecting antigen-activated (i.e. memory)
B cells by detecting CD27. They use CD138 to detect plasma cells, which I am not going to gripe about..
present at very low frequency on memory B cells”. Indeed memory B cells in mice are very complex and consist of multiple subtypes. Read Bergmann et al. 2013).
population go up and as disease is inhibited then the memory cell idea surely
marker in mouse.
the percentage of the other stuff goes up, but without looking at the absolute
numbers of cells, we have no idea if this is a indeed a real increase in
numbers. They may be staying the same or going down. However, if we accept that the data
suggests that a population of B cells is less depleted by CD20 depletion.
you in the Eye Test. The control group in one experiment looks like the Test group
in the other experiment and vice versa. The effects last a few days and suggests that the data is all within “experimental wobble” (biological variation),
meaning there is really no or very limited biological impact on the mice.
In this study MOG protein induced disease, claimed to be B cell dependent, is inhibted by CD20 antibody depletion and MOG peptide induced disease claimed to be B cell independent is augmented by CD20 antibody depletion (see below)
However, if the models (MOG peptide) are B cell independent, then why does anti-CD20 have a significant effect?
Adding the two experiments together then suggests that there is no biological effect of depleting CD20 antibody in mice, which I think is probably the case.
So back to the paper. So we have CD20 depletion causing major depletion
of CD27 B cells and inhibition of relapse in humans, however if you actually look at the data there is no/minor impact (increase) on CD27
B cells and no/minor impact on clinical EAE. So actually it all fits. The memory B cells may remain to
be an important subtype of cell. QED.
COI: I have none, but editor of paper is working in same place as an
author….Em…..Rant over 🙁
P.S. If this type of clinical data is indeed experimental wobble then it suggests that the conclusions of a large number of EAE papers that show similar types of clinical effects become meaningless and suggests that there will be little translational value of many EAE studies in predicting efficacy/biology in humans.
But we know this, Don’t we?
P.S.S. If you are a scientist, this is surely a good Journal Club paper as it should teach you a lot on the need to read around papers to understand them and also teach you about data analysis (stats tests used in paper are all wrong as well:-0) and interpretation.
Maybe I have it all wrong